Indian J Pediatr DOI 10.1007/s12098-014-1492-6
ORIGINAL ARTICLE
Treatment of Chronic Phase Chronic Myeloid Leukemia with Imatinib Prasanth Ganesan & Rejiv Rajendranath & Vignesh Kandakumar & Tenali Gnana Sagar
Received: 1 January 2014 / Accepted: 10 May 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Objective To report outcomes of Chronic Myeloid Leukemia (CML) treated with upfront imatinib. Methods Outcomes of children (≤18 y) with chronic phase CML (CML-CP) treated with imatinib over a 5 y (2003– 2008) period were retrospectively analyzed to quantify responses, progression free survival (PFS) and overall survival (OS). Results Thirty-one patients (age range: 6–18 y) received therapy with imatinib 260–300 mg/m2. Thirty (97 %) achieved complete hematological response at a median of 2 mo from start of treatment. Major and complete cytogenetic response rates at 2 y were 82 % and 70 % respectively. After a median follow up of 49.2 mo the 5 year PFS and OS were 68 % and 76 % respectively. Out of the 16 patients with documented Complete Cytogenetic Response (CCR) at 2 y, none progressed during subsequent follow up. There were no serious toxicities. Most patients who progressed, died of the disease. Conclusions Imatinib is a reasonable first line therapy in pediatric CML-CP, which is effective and well tolerated. Outcomes are comparable to those reported from the West. Availability of second line agents and increased access to stem cell transplantation could further improve outcomes.
Keywords Chronic myeloid leukemia . Pediatric . Imatinib . Survival
P. Ganesan (*) : R. Rajendranath : V. Kandakumar : T. G. Sagar Department of Medical Oncology, Cancer Institute (WIA) Sardar Patel, Road Adyar, Chennai 600020, Tamil Nadu, India e-mail: [email protected]
Introduction Tyrosine Kinase Inhibitors (TKIs) constitute standard first-line therapy of adult Chronic Phase Chronic Myeloid Leukemia (CML-CP) [1, 2]. However, the best initial approach in pediatric CML, which constitutes about 3 % of childhood leukemias is controversial [3, 4]. The absence of large randomized trials in this age group has contributed to debates between continued use of TKIs vs. early allogeneic stem cell transplant [4–6]. Recent results in pediatric CML suggest that responses with TKIs are comparable to those obtained in adults [6–11]. At the same time, outcomes of stem cell transplantation have also improved and the latter offers possibility of “cure” which is still elusive with frontline TKI therapy [12, 13]. There is no clear winner at this point in the tradeoff between long term toxicities of an allogeneic stem cell transplant and the concerns about the chronic effects of life-long intake of TKIs [13, 14]. Allogenic transplant was not an option for majority of patients treated at authors’ center during 1990s and early part of 2000 due to multiple factors like cost, limited availability of transplant facilities and absence of large donor registries. On the other hand, Imatinib (Glivec), became available from 2002 through an initiative called the Glivec International Patient Assistance Program (GIPAP) [15]. Imatinib was given to patients either free-of-cost or through heavy subsidization and thus became available for all patients with this diagnosis. In this analysis, the authors looked at the outcome of pediatric patients enrolled in the first 5 y of this program. None of the patients had access to second line TKIs or stem cell transplant at any point, and hence this data reflects natural history of pediatric CML treated with imatinib alone.
Indian J Pediatr
Material and Methods Patients aged ≤ 18 y with a diagnosis of CML-CP who started imatinib between 2003 and 2008 were included. Previous treatment with hydroxyurea was allowed but those who received other agents like busulfan and interferon were excluded. At baseline, all patients underwent history and physical examination, complete blood counts, and bone marrow studies including cytogenetic assessment. Diagnosis of CML was established by the demonstration of the philadelphia chromosome (conventional cytogenetics and/or fluorescent in situ hybridization, FISH) or by the demonstration of the BCRABL protein by qualitative reverse transcriptase polymerase chain reaction. Standard criteria were used to define chronic phase CML [16]. Imatinib was started at a dose of 260–300 mg/m2 (rounded to the nearest 100 mg) in children weighing less than 40 kg and at a flat dose of 400 mg per day in those weighing ≥40 kg. Patients were followed up with regular blood counts, toxicity and response assessments (weekly in the first 4–8 wk, monthly for the next 3 mo and every 3 mo thereafter). Cytogenetic assessment was done 6 monthly using FISH from the peripheral blood. For grade 3–4 toxicity, imatinib was withheld and re-started at a lower dose and re-escalated thereafter depending on tolerance. Patients progressing to accelerated or blast phases received increased doses or were taken off imatinib and started on hydroxyurea. None of the patients had access to stem cell transplantation or second line TKIs. Progression free survival (PFS) was defined as time from start of therapy till the occurrence of accelerated phase/blast crisis (AP/BC) or death due to progressive disease (whichever occurred first) and overall survival was the time from start of therapy till death due to any cause. The last date for the data cut off was December 2012. Survival estimates were done using the Kaplan–Meier method, and the log rank test was used to compare baseline factors for prognostic significance. SPSS software (version 13.0) was used to perform the statistical analysis.
Results Thirty one patients (age ≤18 y) were started on treatment for CML-CP during the study period (Table 1). The median symptom duration prior to presentation was 1 mo (10 d to 12 mo). Majority (90 %) of the patients had low or intermediate risk Sokal score. The patients received the drug through GIPAP and this process required 4–6 wk after establishing the diagnosis of CML. During this interval, patients received oral hydroxyurea (50 mg/kg- titrated as per the white cell count). The median duration of therapy with hydroxyurea was 1 mo (15 d to 10
Table 1 Baseline clinical and laboratory characteristics (n=31) Clinical features
N (%)
Age (years) Age group 0–14 20 (64.5) Age group 15–18 11 (35.5) Male sex 17 (55) Presenting features Abdominal distension/pain 21 (68) Fever 12 (39) Anemic symptoms 5 (16) Weight loss 4 (13) Bone pains 3 (10) Loss of appetite 3 (10) Splenomegaly 31 (100) Hepatomegaly 15 (48) Lymphadenopathy 2 (6.5) Hematological parameters (Peripheral blood) Hemoglobin (g/L) White cell count (×109/L) Platelet count (×109/L) Blast Cell % Eosinophil % Basophil % Sokal risk category Low (score 1.2)
Median (range) 13 (6–18)
93 (42–109) 228 (42–1090) 487 (120–1280) 2 (0–6) 2 (0–10) 2 (0–7)
13 (42) 15 (48) 3 (10)
mo). Five patients received hydroxyurea for ≥2 mo prior to starting imatinib. Median follow up (from the start of imatinib) was 49.2 mo (range, 4.4-86.4 mo). Eighty seven percent and 66 % of patients had more than 24 mo and 36 mo of observation respectively. Thirty (of 31) patients achieved Complete Hematologic Response (CHR) (97 %) at a median of 2 mo (1.5-8). One patient failed to achieve CHR, progressed despite escalation of dose. At the 2-year time point, cytogenetic data was available in 23/31 patients. Eight patients did not undergo cytogenetic assessment at this point (2 had not achieved CHR, 2 had lost CHR at 6 and 8 mo respectively, 2 had defaulted within this period and 2 did not undergo cytogenetic testing). The cumulative incidence of major and complete cytogenetic response (MCR and CCR) at 2 y was 19/23 (82 %) and 16/23 (70 %) respectively. Molecular assessment was done in 11/16 patients who had achieved CCR by 2 y and 6/11 (55 %) had achieved major molecular response. Disease progression to AP or blast phase occurred in 8 patients (5-year PFS 68 %+/− 20 %; Fig. 1a) and 6 of these subsequently died due to progressive disease (5-year OS
Indian J Pediatr
Fig. 1 Kaplan Meier survival graphs for Progression Free Survival (a) and Overall Survival (b)
76 %+/−19 %; Fig. 1b). The drug was well tolerated with no permanent discontinuations for toxicity. On univariate analysis, none of the baseline clinical or laboratory parameters were predictive of the PFS or OS (data not shown). The 5 year PFS in low risk Sokal patients was 72.5 +/−28 % compared to 64+/−26 % in intermediate Sokal group (p=0.506, NS). Among 3 patients with high risk Sokal scores, 1 did not achieve CHR, 1 achieved MCR, while the third defaulted after 18 mo of follow up while still in CHR. Baseline characteristics (including Sokal score) did not predict the attainment of CHR/CCR. Among the patients who had cytogenetic data available at 2 y (N=23), only 1/19 who achieved MCR at 2 y progressed while 3/4 who did not achieve MCR progressed to AP/BC. None of the patients who achieved CCR (N=16) at 2 y progressed during subsequent follow up. Among those progressed (N=8), mutation analysis was done in five patients. Four of these had no detectable mutations and one had the T315I mutation. Three patients had grade 3 neutropenia in the first 3 mo of treatment and 2 had grade 3 thrombocytopenia. Both
responded to brief interruption of medication. Otherwise there was no other grade 3/4 hematological or non-hematological toxicity. The commonest non-hematological toxicities recorded (all grade 1–2) were musculoskeletal pain (30 %), gastrointestinal toxicity (27 %), fluid retention (8 %) and hypopigmentation of the skin (24 %).
Discussion Though imatinib has been used for the last 15 y in the treatment of CML, literature pertaining to its role in the pediatric subset of patients is limited. The authors found that imatinib is highly active in pediatric CML with 97 % of treated patients achieving CHR. Survival outcomes (5-year PFS and OS of 68 % and 75 % respectively) in the index patients are comparable to those reported from the West (Table 2). The variability in results between studies shown in Table 2 can be explained based on differences in the population of patients included in these studies- some had newly diagnosed, treatment naïve patients [11] while others
Table 2 Published studies of imatinib in Pediatric CML-CP Study
N
CHR
CCR
Median follow up
Outcome
Champagne [7] Millot [10] Millot [8] Champagne [11] Current study
14 30a 44 51 31
NR 80 % 94 % 80%b 97 %
83 % 60 % 77 % 72%c 70%d
NR 28 mo 31 mo NR 48 mo
13 alive, 1 died 1 y OS 95 % 1 patient died 3 y PFS 72 %, 3 y OS 92 % 5 y PFS 68 %, 5 y OS 75 %,
a
73% in CP (mostly late chronic phase or in relapse after stem cell transplantation), b CHR at end of course 2, c As best response, d At 2 y
CHR Complete hematologic response; CCR Complete cytogenetic response; CP Chronic phase; NR Not reported; OS Overall survival; PFS Progression free survival
Indian J Pediatr
included patients in late chronic phase or even those who had relapsed after stem cell transplant [10]. Cross-trial comparisons are treacherous in CML due to multiple reasons including variable definitions of outcome measures [17]. However, other studies have suggested that adolescents and young adults with CML may not perform as well as adults [18]. Little data exists on prognostic factors in pediatric CML in the TKI-era. The authors did find a correlation between Sokal score and attainment of therapeutic goals, though this was not statistically significant. No other pre-treatment factor was prognostic. The prognostic value of Sokal score is not wellestablished in children and it would be interesting to follow this in future studies. All the children tolerated imatinib well with no permanent discontinuations due to toxicity. However, few required brief interruptions; for grade 3–4 myelosuppression. A striking side effect was hypopigmentation of skin which was observed in 24 % patients which has been reported earlier from India [19]. Imatinib, as first line therapy in pediatric CML allows ease of administration, excellent safety and positive outcomes in about three-quarters of patients. The vexing problem of treatment related mortality (TRM) is almost non-existent in imatinib therapy as compared to an allogeneic stem cell transplant where even the most competent centers report 5–10 % TRM due to complications of the procedure [12, 13]. Though transplant offers possibility of “cure”, quality and quantity of life may be limited by short and long term complications of the procedure. More recent reviews of pediatric CML suggest that transplant might be reserved for patients who do not do well with imatinib [6]. This study involves small number of patients and the analysis is retrospective. Also, economic constraints precluded regular cytogenetic assessments and hence data on the kinetics of these responses is not available. However, the authors have included a uniform population of patients who received similar therapy and had a long follow up. The fact that none of the patients had access to stem cell transplant and/ or second line TKIs means that this study reflects the natural history of pediatric CML treated with imatinib alone. It is concluded that imatinib is a reasonable first line treatment option in pediatric CML, especially in resource constrained settings where access to stem cell transplant facilities is limited. Acknowledgements The authors acknowledge the Glivec International Patient Assistance Program for providing imatinib for the patients. Contributions PG: Collection of data, analysis, writing manuscript; RR: Collection of data, analysis; VK: Collection of data; TGS: Writing manuscript and will act as guarantor for this paper. Conflict of Interest None. Source of Funding None.
References 1. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. 2. Cervantes F, Mauro M. Practical management of patients with chronic myeloid leukemia. Cancer. 2011;117:4343–54. 3. Ries LA, Smith MA, Gurney JG. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub. No. 99–4649.; 1999. 4. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:368–76. 5. Suttorp M, Yaniv I, Schultz KR. Controversies in the treatment of CML in children and adolescents: TKIs versus BMT? Biol Blood Marrow Transplant. 2011;17:S115–22. 6. Andolina JR, Neudorf SM, Corey SJ. How I treat childhood CML. Blood. 2012;119:1821–30. 7. Champagne MA, Capdeville R, Krailo M, Qu W, Peng B, Rosamilia M, et al. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children’s Oncology Group phase 1 study. Blood. 2004;104:2655– 60. 8. Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y, et al. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. J Clin Oncol. 2011;29:2827–32. 9. Belgaumi AF, Al-Shehri A. Clinical characteristics and treatment outcome of pediatric patients with chronic myeloid leukemia. Haematologica. 2010;95:e4. 10. Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, Békassy AN, et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia. 2006;20:187–92. 11. Champagne MA, Fu CH, Chang M, Chen H, Gerbing RB, Alonzo TA, et al. Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2011;57:56–62. 12. Millot F, Esperou H, Bordigoni P, Dalle JH, Michallet M, Michel G, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant. 2003;32:993–9. 13. Cwynarski K, Roberts IA, Iacobelli S, van Biezen A, Brand R, Devergie A, et al. Stem cell transplantation for chronic myeloid leukemia in children. Blood. 2003;102:1224–31. 14. Shima H, Tokuyama M, Tanizawa A, Tono C, Hamamoto K, Muramatsu H, et al. Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr. 2011;159:676–81. 15. Glivec® International Patient Assistance Program (GIPAP).http:// http://www.themaxfoundation.org/gipap/Default.aspx. Accessed 1Dec 2013. 16. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20. 17. Kantarjian H, O’Brien S, Jabbour E, Shan J, Ravandi F, Kadia T, et al. Impact of treatment end point definitions on perceived differences in
Indian J Pediatr long-term outcome with tyrosine kinase inhibitor therapy in chronic myeloid leukemia. J Clin Oncol. 2011;29:3173–8. 18. Pemmaraju N, Kantarjian H, Shan J, Jabbour E, QuintasCardama A, Verstovsek S, et al. Analysis of outcomes in adolescents and young adults with chronic myelogenous
leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematologica. 2012;97:1029–35. 19. Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai V. Pigmentary changes in chronic myeloid leukemia patients treated with imatinib mesylate. Ann Oncol. 2004;15:358–9.
ORIGINAL ARTICLE
Treatment of Chronic Phase Chronic Myeloid Leukemia with Imatinib Prasanth Ganesan & Rejiv Rajendranath & Vignesh Kandakumar & Tenali Gnana Sagar
Received: 1 January 2014 / Accepted: 10 May 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Objective To report outcomes of Chronic Myeloid Leukemia (CML) treated with upfront imatinib. Methods Outcomes of children (≤18 y) with chronic phase CML (CML-CP) treated with imatinib over a 5 y (2003– 2008) period were retrospectively analyzed to quantify responses, progression free survival (PFS) and overall survival (OS). Results Thirty-one patients (age range: 6–18 y) received therapy with imatinib 260–300 mg/m2. Thirty (97 %) achieved complete hematological response at a median of 2 mo from start of treatment. Major and complete cytogenetic response rates at 2 y were 82 % and 70 % respectively. After a median follow up of 49.2 mo the 5 year PFS and OS were 68 % and 76 % respectively. Out of the 16 patients with documented Complete Cytogenetic Response (CCR) at 2 y, none progressed during subsequent follow up. There were no serious toxicities. Most patients who progressed, died of the disease. Conclusions Imatinib is a reasonable first line therapy in pediatric CML-CP, which is effective and well tolerated. Outcomes are comparable to those reported from the West. Availability of second line agents and increased access to stem cell transplantation could further improve outcomes.
Keywords Chronic myeloid leukemia . Pediatric . Imatinib . Survival
P. Ganesan (*) : R. Rajendranath : V. Kandakumar : T. G. Sagar Department of Medical Oncology, Cancer Institute (WIA) Sardar Patel, Road Adyar, Chennai 600020, Tamil Nadu, India e-mail: [email protected]
Introduction Tyrosine Kinase Inhibitors (TKIs) constitute standard first-line therapy of adult Chronic Phase Chronic Myeloid Leukemia (CML-CP) [1, 2]. However, the best initial approach in pediatric CML, which constitutes about 3 % of childhood leukemias is controversial [3, 4]. The absence of large randomized trials in this age group has contributed to debates between continued use of TKIs vs. early allogeneic stem cell transplant [4–6]. Recent results in pediatric CML suggest that responses with TKIs are comparable to those obtained in adults [6–11]. At the same time, outcomes of stem cell transplantation have also improved and the latter offers possibility of “cure” which is still elusive with frontline TKI therapy [12, 13]. There is no clear winner at this point in the tradeoff between long term toxicities of an allogeneic stem cell transplant and the concerns about the chronic effects of life-long intake of TKIs [13, 14]. Allogenic transplant was not an option for majority of patients treated at authors’ center during 1990s and early part of 2000 due to multiple factors like cost, limited availability of transplant facilities and absence of large donor registries. On the other hand, Imatinib (Glivec), became available from 2002 through an initiative called the Glivec International Patient Assistance Program (GIPAP) [15]. Imatinib was given to patients either free-of-cost or through heavy subsidization and thus became available for all patients with this diagnosis. In this analysis, the authors looked at the outcome of pediatric patients enrolled in the first 5 y of this program. None of the patients had access to second line TKIs or stem cell transplant at any point, and hence this data reflects natural history of pediatric CML treated with imatinib alone.
Indian J Pediatr
Material and Methods Patients aged ≤ 18 y with a diagnosis of CML-CP who started imatinib between 2003 and 2008 were included. Previous treatment with hydroxyurea was allowed but those who received other agents like busulfan and interferon were excluded. At baseline, all patients underwent history and physical examination, complete blood counts, and bone marrow studies including cytogenetic assessment. Diagnosis of CML was established by the demonstration of the philadelphia chromosome (conventional cytogenetics and/or fluorescent in situ hybridization, FISH) or by the demonstration of the BCRABL protein by qualitative reverse transcriptase polymerase chain reaction. Standard criteria were used to define chronic phase CML [16]. Imatinib was started at a dose of 260–300 mg/m2 (rounded to the nearest 100 mg) in children weighing less than 40 kg and at a flat dose of 400 mg per day in those weighing ≥40 kg. Patients were followed up with regular blood counts, toxicity and response assessments (weekly in the first 4–8 wk, monthly for the next 3 mo and every 3 mo thereafter). Cytogenetic assessment was done 6 monthly using FISH from the peripheral blood. For grade 3–4 toxicity, imatinib was withheld and re-started at a lower dose and re-escalated thereafter depending on tolerance. Patients progressing to accelerated or blast phases received increased doses or were taken off imatinib and started on hydroxyurea. None of the patients had access to stem cell transplantation or second line TKIs. Progression free survival (PFS) was defined as time from start of therapy till the occurrence of accelerated phase/blast crisis (AP/BC) or death due to progressive disease (whichever occurred first) and overall survival was the time from start of therapy till death due to any cause. The last date for the data cut off was December 2012. Survival estimates were done using the Kaplan–Meier method, and the log rank test was used to compare baseline factors for prognostic significance. SPSS software (version 13.0) was used to perform the statistical analysis.
Results Thirty one patients (age ≤18 y) were started on treatment for CML-CP during the study period (Table 1). The median symptom duration prior to presentation was 1 mo (10 d to 12 mo). Majority (90 %) of the patients had low or intermediate risk Sokal score. The patients received the drug through GIPAP and this process required 4–6 wk after establishing the diagnosis of CML. During this interval, patients received oral hydroxyurea (50 mg/kg- titrated as per the white cell count). The median duration of therapy with hydroxyurea was 1 mo (15 d to 10
Table 1 Baseline clinical and laboratory characteristics (n=31) Clinical features
N (%)
Age (years) Age group 0–14 20 (64.5) Age group 15–18 11 (35.5) Male sex 17 (55) Presenting features Abdominal distension/pain 21 (68) Fever 12 (39) Anemic symptoms 5 (16) Weight loss 4 (13) Bone pains 3 (10) Loss of appetite 3 (10) Splenomegaly 31 (100) Hepatomegaly 15 (48) Lymphadenopathy 2 (6.5) Hematological parameters (Peripheral blood) Hemoglobin (g/L) White cell count (×109/L) Platelet count (×109/L) Blast Cell % Eosinophil % Basophil % Sokal risk category Low (score 1.2)
Median (range) 13 (6–18)
93 (42–109) 228 (42–1090) 487 (120–1280) 2 (0–6) 2 (0–10) 2 (0–7)
13 (42) 15 (48) 3 (10)
mo). Five patients received hydroxyurea for ≥2 mo prior to starting imatinib. Median follow up (from the start of imatinib) was 49.2 mo (range, 4.4-86.4 mo). Eighty seven percent and 66 % of patients had more than 24 mo and 36 mo of observation respectively. Thirty (of 31) patients achieved Complete Hematologic Response (CHR) (97 %) at a median of 2 mo (1.5-8). One patient failed to achieve CHR, progressed despite escalation of dose. At the 2-year time point, cytogenetic data was available in 23/31 patients. Eight patients did not undergo cytogenetic assessment at this point (2 had not achieved CHR, 2 had lost CHR at 6 and 8 mo respectively, 2 had defaulted within this period and 2 did not undergo cytogenetic testing). The cumulative incidence of major and complete cytogenetic response (MCR and CCR) at 2 y was 19/23 (82 %) and 16/23 (70 %) respectively. Molecular assessment was done in 11/16 patients who had achieved CCR by 2 y and 6/11 (55 %) had achieved major molecular response. Disease progression to AP or blast phase occurred in 8 patients (5-year PFS 68 %+/− 20 %; Fig. 1a) and 6 of these subsequently died due to progressive disease (5-year OS
Indian J Pediatr
Fig. 1 Kaplan Meier survival graphs for Progression Free Survival (a) and Overall Survival (b)
76 %+/−19 %; Fig. 1b). The drug was well tolerated with no permanent discontinuations for toxicity. On univariate analysis, none of the baseline clinical or laboratory parameters were predictive of the PFS or OS (data not shown). The 5 year PFS in low risk Sokal patients was 72.5 +/−28 % compared to 64+/−26 % in intermediate Sokal group (p=0.506, NS). Among 3 patients with high risk Sokal scores, 1 did not achieve CHR, 1 achieved MCR, while the third defaulted after 18 mo of follow up while still in CHR. Baseline characteristics (including Sokal score) did not predict the attainment of CHR/CCR. Among the patients who had cytogenetic data available at 2 y (N=23), only 1/19 who achieved MCR at 2 y progressed while 3/4 who did not achieve MCR progressed to AP/BC. None of the patients who achieved CCR (N=16) at 2 y progressed during subsequent follow up. Among those progressed (N=8), mutation analysis was done in five patients. Four of these had no detectable mutations and one had the T315I mutation. Three patients had grade 3 neutropenia in the first 3 mo of treatment and 2 had grade 3 thrombocytopenia. Both
responded to brief interruption of medication. Otherwise there was no other grade 3/4 hematological or non-hematological toxicity. The commonest non-hematological toxicities recorded (all grade 1–2) were musculoskeletal pain (30 %), gastrointestinal toxicity (27 %), fluid retention (8 %) and hypopigmentation of the skin (24 %).
Discussion Though imatinib has been used for the last 15 y in the treatment of CML, literature pertaining to its role in the pediatric subset of patients is limited. The authors found that imatinib is highly active in pediatric CML with 97 % of treated patients achieving CHR. Survival outcomes (5-year PFS and OS of 68 % and 75 % respectively) in the index patients are comparable to those reported from the West (Table 2). The variability in results between studies shown in Table 2 can be explained based on differences in the population of patients included in these studies- some had newly diagnosed, treatment naïve patients [11] while others
Table 2 Published studies of imatinib in Pediatric CML-CP Study
N
CHR
CCR
Median follow up
Outcome
Champagne [7] Millot [10] Millot [8] Champagne [11] Current study
14 30a 44 51 31
NR 80 % 94 % 80%b 97 %
83 % 60 % 77 % 72%c 70%d
NR 28 mo 31 mo NR 48 mo
13 alive, 1 died 1 y OS 95 % 1 patient died 3 y PFS 72 %, 3 y OS 92 % 5 y PFS 68 %, 5 y OS 75 %,
a
73% in CP (mostly late chronic phase or in relapse after stem cell transplantation), b CHR at end of course 2, c As best response, d At 2 y
CHR Complete hematologic response; CCR Complete cytogenetic response; CP Chronic phase; NR Not reported; OS Overall survival; PFS Progression free survival
Indian J Pediatr
included patients in late chronic phase or even those who had relapsed after stem cell transplant [10]. Cross-trial comparisons are treacherous in CML due to multiple reasons including variable definitions of outcome measures [17]. However, other studies have suggested that adolescents and young adults with CML may not perform as well as adults [18]. Little data exists on prognostic factors in pediatric CML in the TKI-era. The authors did find a correlation between Sokal score and attainment of therapeutic goals, though this was not statistically significant. No other pre-treatment factor was prognostic. The prognostic value of Sokal score is not wellestablished in children and it would be interesting to follow this in future studies. All the children tolerated imatinib well with no permanent discontinuations due to toxicity. However, few required brief interruptions; for grade 3–4 myelosuppression. A striking side effect was hypopigmentation of skin which was observed in 24 % patients which has been reported earlier from India [19]. Imatinib, as first line therapy in pediatric CML allows ease of administration, excellent safety and positive outcomes in about three-quarters of patients. The vexing problem of treatment related mortality (TRM) is almost non-existent in imatinib therapy as compared to an allogeneic stem cell transplant where even the most competent centers report 5–10 % TRM due to complications of the procedure [12, 13]. Though transplant offers possibility of “cure”, quality and quantity of life may be limited by short and long term complications of the procedure. More recent reviews of pediatric CML suggest that transplant might be reserved for patients who do not do well with imatinib [6]. This study involves small number of patients and the analysis is retrospective. Also, economic constraints precluded regular cytogenetic assessments and hence data on the kinetics of these responses is not available. However, the authors have included a uniform population of patients who received similar therapy and had a long follow up. The fact that none of the patients had access to stem cell transplant and/ or second line TKIs means that this study reflects the natural history of pediatric CML treated with imatinib alone. It is concluded that imatinib is a reasonable first line treatment option in pediatric CML, especially in resource constrained settings where access to stem cell transplant facilities is limited. Acknowledgements The authors acknowledge the Glivec International Patient Assistance Program for providing imatinib for the patients. Contributions PG: Collection of data, analysis, writing manuscript; RR: Collection of data, analysis; VK: Collection of data; TGS: Writing manuscript and will act as guarantor for this paper. Conflict of Interest None. Source of Funding None.
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